1. Field of the Invention
The present invention relates to a new method for detecting Alzheimer's disease. Specifically, the present invention relates to a method for detecting or diagnosing Alzheimer's disease using the inactivation of STAT3 protein as an indication.
The present invention also relates to a method for screening for an agent for treating Alzheimer's disease, using the activation of STAT3 protein as an indication.
The present invention further relates to a pharmaceutical composition for treating Alzheimer's disease, comprising a drug that activates the STAT3 protein.
2. Background of the Invention
Alzheimer's disease (AD) is the most common neurodegenerative disease, which is characterized clinically by progressive memory loss and cognitive dysfunction and pathologically by senile plaques, neurofibrillary tangles, and neuron death (Mattson M P (2004) Nature 430: 631-639).
In the previous studies, we have prepared Colivelin by attaching activity-dependent neurotrophic factor (ADNF) to a potent Human (HM) derivative (Chiba T, Yamada M, Hashimoto Y, Sato M, Sasabe J, Kita Y, Terashita K, Aiso S, Nishimoto I, Matsuoka M (2005) J Neurosci 25: 10252-10261). HN is a neuroprotection factor isolated and identified from an occipital lobe of an Alzheimer's disease patient and has antagonistic effects on various types of Alzheimer's disease-relevant neurotoxicity (Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I (2001) Proc Natl Acad Sci U.S.A. 98: 6336-6341). Furthermore, we have demonstrated that HN-mediated neuroprotection takes place via the activation of STAT3 molecule in vitro (Chiba T et al., (2005) above; Hashimoto Y, Suzuki H, Aiso S, Niikura T, Nishimoto I, Matsuoka M (2005) Life Sci 77: 3092-3104).
STAT (signal transducer and activator of transcription) is a protein molecule that broadly exists in multicellular organisms and plays roles in a variety of cellular events, such as development, cell proliferation, and cell death (Stephanou A, Latchman D S (2005) Growth Factors 23(3): 177-82). Seven different STAT family members have been identified to date: STAT1, STAT2, STAT3, STAT4, STAT5α, STAT5β, and STAT6. These molecules are thought to be important molecules of cytokine receptor-mediated signaling. Of these, STAT3 seems to be responsible for particularly important functions in vivo because STAT3 knockout mice showed a phenotype of embryonic lethality at the early stage of development (Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S (1997) Proc Natl Acad Sci U.S.A. 15; 94(8): 38014). In addition, it has been reported that STAT-3 bears a function to restrict apoptosis in various types of cells (Chen R H, Chang M C, Su Y H, Tsai Y T, Kuo M L (1999) J Biol Chem. 274(33): 23013-9; Grandis J R, Drenning S D, Zeng Q, Watkins S C, Melhem M F, Endo S, Johnson D E, Huang L, He Y, Kim J D (2000) Proc Natl Acad Sci U.S.A. 97(8): 4227-32).
We have now examined the pathological relationship between Alzheimer's disease and STAT3 protein (i.e., the pathological contribution of STAT3), using brain tissues of Alzheimer's disease animal models and Alzheimer's disease patients. STAT3 is a molecule having important cellular functions including an anti-apoptotic function (i.e., cell survival) in various types of cells. However, the relationship of STAT3 with the pathological conditions of Alzheimer's disease has remained unknown.